S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof

ABSTRACT

A process for preparing S type 2-substituted hydroxy-2-indolidinyl-butyric ester compound  II!: ##STR1## wherein R o  is residue of nitrogen-containing fused heterocyclic carboxylic acid having absolute configuration of &#34;R&#34;(in which the nitrogen atom is protected), R 1  and R 2  are lower alkyl group, and E is ester residue, which is useful as an intermediate for preparing camptothecin derivatives having antitumor activities, which comprises 2-ethylating 2-substituted hydroxy-2-indolidinylacetic ester compound  I!: ##STR2## wherein the symbols are as defined above.

FIELD OF INVENTION

This invention relates to an S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound and a process for thepreparation thereof. More particularly, it relates to an S type2-substituted hydroxy-2-indolidinyl-butyric ester compound which isuseful as an intermediate for preparing camptothecin derivatives havingantitumor activities and a process for preparing said compound in highyield and in high stereoselectivity.

PRIOR ART

There is known a process for preparing camptothecin derivatives havingantitumor activities by Friedlaender reaction (cf. EP-A-540099,EP-A-296597, JP-A-6-87746, WO 90/03169, EP-A-418099), wherein it hasbeen investigated to find processes for preparing S type4-hydroxypyranoindolidine compounds of the formula VIII! which areimportant as an intermediate: ##STR3##

Besides, it is reported, for example, in EP-A-220601 that an S type 2-(R)-N-tosyl-prolyloxy!-2-indolidinylbutyric ester compound of theformula XX!: ##STR4## may be prepared by brominating at 2-position of a2-indolidinylacetic ester compound of the formula XX!: ##STR5## andreacting the resultant with an (R)-N-tosylproline and further ethylatingat 2-position of the reaction product, and further that a camptothecinderivative is prepared from said compound via an S type4-hydroxypyranoindolidine compound VIII!.

However, according to this process, the desired S type 2-(R)-N-tosylprolyloxy!-2-indolidinylbutyric ester compound XXI! is merelyobtained in an amount of 2.6-4.6 times larger (44-64% d.e.) than that ofa diastereomer having an absolute configuration of "R" at 2-positionwhich is simultaneously prepared, and the S type compound is isolatedtherefrom in a further lower yield, only 56%, by a fractionalrecrystallization cf. Organic Synthetic Chemistry, vol. 49, No. 11, pp.1013-1020, 1991!.

BRIEF SUMMARY OF THE INVENTION

This invention provides an S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound useful as an intermediatefor preparing camptothecin derivatives in a high yield and in a highstereoselectivity.

DETAILED DESCRIPTION OF THE INVENTION

According to this invention, the desired S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound of the formula II!: ##STR6##can be prepared by reacting a 2-halo-2-indolidinylacetic ester compoundof the formula III!: ##STR7## wherein X is a halogen atom, R¹ and R² area lower alkyl group, and E is an ester residue, with an R typenitrogen-containing fused heterocyclic carboxylic acid compound of theformula IV!:

    R.sup.o OH                                                  IV!

wherein R^(o) is a residue of a nitrogen-containing fused heterocycliccarboxylic acid having an absolute configuration of "R" which isobtained by removing hydroxy group from the carboxyl group of saidcarboxylic acid compound (in which the nitrogen atom contained in theresidue is protected) or a salt thereof to give a 2-substitutedhydroxy-2-indolidinylacetic ester compound of the formula I!: ##STR8##wherein the symbols are as defined above, and then ethylating 2-positionof the resultant compound I!.

The process of this invention is characteristic in that the2-substituted hydroxy-2-indolidinylacetic ester compound I! issterically bulky at the acetal moiety and has a sterically bulkysubstituent containing an optically active nitrogen-containing fusedheterocyclic ring at 2-position thereof and hence it is ethylated withhigh yield and high stereoselectivity at 2-position, and thereby thedesired S type 2-substituted hydroxy-2-indolidinylbutyric ester compoundII! is obtained in a high selectivity such as 9 times or more higher(80% d.e. or more) than the diastereomer having an absoluteconfiguration of "R" at 2-position. Particularly, when the group "Y" inthe substituent R^(o) in the compound I! is a 4-nitrophenylsulfonylgroup or a 4-biphenyl sulfonyl group, the desired compound is obtainedin much higher stereoselectivity of 20 times (90% d.e.) or 15.2 times(88% d.e.) higher, respectively and in much higher isolation yield of75% or 76%, respectively.

The R type nitrogen-containing fused heterocyclic carboxylic acidcompound IV! in this invention means a compound having a carboxyl groupbound to a nitrogen-containing fused heterocyclic ring (the nitrogenatom contained in said compound is protected), and the carbon atom boundwith the carboxyl group has an absolute configuration of "R", and thenitrogen-containing fused heterocyclic ring includes a benzene-fusednitrogen-containing heterocyclic ring, for example, atetrahydroisoquinoline ring, a tetra-hydroquinoline ring, adihydroquinoline ring, or an indoline ring.

Suitable example of the nitrogen-containing fused heterocycliccarboxylic acid compound having an absolute configuration of "R" is acompound of the formula XIX!: ##STR9## wherein n is 0 or 1, and Y is asubstituted or unsubstituted arylsulfonyl group or a lower alkylsulfonylgroup.

The above compound XIX! wherein n is 1 means anN-substituted-1,2,3,4-tetrahydro-3-ylquinolinecarboxylic acid, and thecompound XIX! wherein n is 0 means an N-substituted 2-indolinecarboxylicacid. The substituent "Y" on the nitrogen atom of the above compoundXIX! includes a phenylsulfonyl, naphthylsulfonyl or biphenylylsulfonylgroup (which may optionally be substituted by a member selected from anitro group, a lower alkyl group, a lower alkoxy group, a cycloalkylgroup, a halogen atom, or a thienyl group), or a lower alkylsulfonylgroup, for example, a phenylsulfonyl group, a tosyl group, a2,4,6-trimethylphenylsulfonyl group, a 4-nitrophenylsulfonyl group, a4-chlorophenylsulfonyl group, a 4-methoxyphenylsulfonyl group, a4-cyclohexylphenylsulfonyl group, a 4-(3-thienyl)phenylsulfonyl group, a2-naphthylsulfonyl group, a 4-biphenylylsulfonyl group, a methylsulfonylgroup, and an ethylsulfonyl group.

Among the above, preferred compounds are a compound XIX! wherein thesubstituent "Y" on the nitrogen atom is a tosyl group, a2-naphthyl-sulfonyl group, a 2,4,6-trimethylphenylsulfonyl group, a4-biphenylylsulfonyl group, or a 4-nitrophenylsulfonyl group and n is 1,and a compound XIX! wherein the substituent "Y" on the nitrogen atom isa tosyl group and n is 0. Particularly preferred compounds are acompound XIX! wherein the substituent "Y" on the nitrogen atom is a4-biphenylylsulfonyl group or a 4-nitrophenylsulfonyl group and n is 1.

The R¹ and R² are a lower alkyl group, such as a methyl group, an ethylgroup, a propyl group, an isopropyl group, an n-butyl group, an isobutylgroup; X is a halogen atom such as chlorine, bromine, iodine. The Eincludes any conventional ester residues, for example lower alkyl groupssuch as a methyl group, an ethyl group, a propyl group, an isopropylgroup, an n-butyl group, or an isobutyl group. Among them, preferablegroups are R¹ and R² being a methyl group, X being a chlorine atom or abromine atom, and E being a methyl group or an ethyl group.

The reaction of the 2-halo-2-indolidinylacetic ester compound III! andthe R type nitrogen-containing fused heterocyclic carboxylic acidcompound IV! or a salt thereof is carried out in a suitable solvent.

The salt of the R-type nitrogen-containing fused heterocyclic carboxylicacid compound IV! includes an alkali metal salt (e.g. potassium salt,sodium salt), an alkaline earth metal salt (e.g. magnesium salt, calciumsalt).

The reaction of the 2-halo-2-indolidinylacetic ester compound III! andthe R type nitrogen-containing fused heterocyclic carboxylic acidcompound IV! or a salt thereof is preferably carried out in the presenceor absence of an acid scavenger. Suitable examples of the acid scavengerare inorganic bases, such as an alkali metal hydride (e.g. lithiumhydride, sodium hydride, potassium hydride), an alkali metal amide (e.g.lithium amide, sodium amide, potassium amide), an alkali metal carbonate(e.g. sodium carbonate, potassium carbonate), an alkali metal hydrogencarbonate (e.g. sodium hydrogen carbonate, potassium hydrogencarbonate), an alkali metal hydroxide (e.g. sodium hydroxide, potassiumhydroxide, lithium hydroxide), and organic bases, such as an alkalimetal alkoxide (e.g. sodium ethoxide, potassium tert-butoxide), analkali metal alkylamide (e.g. lithium diisopropylamide), atrialkyl-amine (e.g. triethylamine, trimethylamine), anN,N-dialkylaniline (e.g. N,N-dimethylaniline), 1,8-diazabicyclo5.4.0!undeca-7-ene.

The solvent used in the reaction includes any conventional solvent whichdoes not affect on the reaction, and suitable examples are an amide typesolvent (e.g. dimethylformamide, dimethylacetamide), an ether solvent(e.g. tetra-hydrofuran, dimethyl ether, dioxane). The reaction isusually carried out at a temperature of from 20 to 100° C., preferablyfrom 50 to 70° C.

The subsequent 2-ethylation of the 2-substitutedhydroxy-2-indolidinylacetic ester compound I! is carried out in asuitable solvent in the presence of an acid scavenger.

The ethylating agent is preferably an ethyl halide (e.g. ethyl iodide,ethyl bromide), more preferably ethyl iodide. The acid scavenger is thesame agents as mentioned above for the reaction of the2-halo-2-indolidinylacetic ester compound III! and the R typenitrogen-containing fused heterocyclic carboxylic acid compound IV! or asalt thereof, and particularly preferable agent is sodium hydride.

The solvent used in the reaction includes any conventional solvent whichdoes not affect on the reaction, and suitable examples are an amide typesolvent (e.g. dimethylformamide, dimethylacetamide), a sulfoxide solvent(e.g. dimethylsulfoxide), an ether solvent (e.g. tetrahydrofuran,dioxane, dimethyl ether), an aromatic hydrocarbon solvent (e.g. toluene,xylene, benzene, chloro-benzene), or a mixture thereof, and particularlypreferable solvent is a mixture of dimethylacetamide and toluene. Thereaction is usually carried out at a temperature of from -10 to 50° C.,particularly preferably at a room temperature.

The desired compound II! in a crude form thus obtained can easily bepurified by recrystallization to give a highly purified compound II!.

The S type 2-substituted hydroxy-2-indolidinylbutyric ester compound II!thus obtained is subjected to a catalytic reduction to reduce the cyanogroup thereof and then subjected to alkanoylation to give an S type2-substituted hydroxy-2-(6-substituted aminomethylindolidinyl)butyricester compound of the formula V!: ##STR10## wherein R³ is a loweralkanoyl group, and other symbols are as defined above, and theresultant is subjected to nitrosation reaction and rearrangement to givean S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound of the formula VI!:##STR11## wherein the symbols are as defined above. The compound VI! isthen subjected to an intramolecular cyclization reaction, and thereafteror at the same time as the cyclization reaction, the acetal groupthereof is converted into a ketone group to give an S type 4-substitutedhydroxypyranoindolidine compound of the formula VII!: ##STR12## whereinthe symbol is as defined above.

The above compound VII! is subjected to Friedlaender reaction togetherwith an o-acylaniline compound of the formula XIV!: ##STR13## whereinthe groups R⁵ -R⁹ are each a hydrogen atom or a substituent beingoptionally protected, in a conventional manner to give a camptothecincompound having a substituent on the 20-hydroxy group of the formulaXV!: ##STR14## wherein the symbols are as defined above, and thecompound XV! is subjected to removal of R^(o) group and further, whenthe groups R⁵ -R⁹ are protected, subjected to removal of the protectinggroup, and further optionally to conversion into a salt thereof to givea camptothecin compound of the formula XVI!: ##STR15## wherein thegroups R⁵¹ -R⁹¹ are each a hydrogen atom or an unprotected substituent,or a salt thereof.

Besides, it is assumed that in the above intramolecular cyclizationreaction of the S type 2-substituted hydroxy-2-(6-substitutedhydroxymethyl-indolidinyl)butyric ester compound VI!, there is produceda compound of the following formula: ##STR16## wherein the symbols areas defined above.

The camptothecin compound XVI! or a salt thereof may also be prepared bya process comprising the following steps:

(a-1) subjecting the S type 4-substituted hydroxypyranoindolidinecompound VII! to removal of the group R^(o), or

(a-2) subjecting the S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound VI! to an esterhydrolysis to give an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound of theformula IX!: ##STR17## wherein the symbols are as defined above,subjecting the compound IX! to an intramolecular cyclization reactionand thereafter or simultaneously with the cyclization reactionconverting the acetal group thereof into a ketone group, and furtheroptionally converting the product into a salt thereof to give an S type4-hydroxypyranoindolidine compound of the formula VIII!: ##STR18## or asalt thereof, (b) subjecting the compound VIII! to Friedlaender reactiontogether with an o-acylaniline compound XIV! in a usual manner to give acamptothecin compound of the formula XVII!: ##STR19## wherein thesymbols are as defined above, (c) subjecting the compound XVII! toremoval of the protecting group of the groups R⁵ -R⁹, when these groupscontain a protecting group, and further

(d) optionally converting the product into a salt thereof.

Alternatively, the camptothecin compound XVI! or a salt thereof may beprepared by a process comprising the following steps:

(i) subjecting the S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound VI! to an esterhydrolysis to give an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound IX! or asalt thereof,

(ii) subjecting the compound IX! to an intramolecular cyclizationreaction and further optionally converting the product into a saltthereof to give an S type 4-hydroxypyranoindolidine compound of theformula X!: ##STR20## wherein the symbols are as defined above, or asalt thereof, (iii) reacting the compound X! with a lower alkanoic acidof the formula XI!:

    R.sup.4 OH                                                  XI!

wherein R⁴ is a lower alkanoyl group, or a reactive derivative thereofto give an S type 4-alkanoyloxypyranoindolidine compound of the formulaXII!: ##STR21## wherein the symbols are as defined above, (iv)converting the acetal group of said compound XII! into a ketone group togive an S type 4-alkanoyloxypyranoindolidine compound of the formulaXIII!: ##STR22## wherein the symbols are as defined above, (v)subjecting the compound XIII! to Friedlaender reaction together with ano-acylaniline compound XIV! in a usual manner to give a camptothecincompound having a substituent on the 20-hydroxy group of the formulaXVIII!: ##STR23## wherein the symbols are as defined above, (vi)subjecting the compound XVIII! to removal of the group R⁴ and further toremoval of the protecting group of the groups R⁵ -R⁹, when these groupscontain a protecting group, and further

(vii) optionally converting the product into a salt thereof.

In the above compounds, the groups R⁵ -R⁹ include any substituents likein known camptothecin derivatives (cf. for example, EP-A-540099,EP-A-296597, JP-A-6-228141, WO 90/03169, EP-A-418099) as well as in thecamptothecin derivatives as disclosed in European Patent PublicationNos. 757049 and 781781, for example, the following groups:

(a) the adjacent two groups among the R⁵ -R⁹ combine to form a straightchain or branched chain alkylene group having 2 to 6 carbon atoms, orare both a hydrogen atom, and one of the remaining groups is --Q_(q)--Alk_(p) --R¹⁰, and other two of the remaining groups are a hydrogenatom, a substituted or unsubstituted lower alkyl group, or a halogenatom,

(b) the adjacent two groups among the R⁵ -R⁹ combine to form a straightchain or branched chain alkylene group having 2 to 6 carbon atoms, andany one carbon atom in the alkylene group is substituted by a group ofthe formula: --Q_(q) --Alk_(p) --R¹⁰, and the remaining three groups ofthe R⁵ -R⁹ are a hydrogen atom, a substituted or unsubstituted loweralkyl group, or a halogen atom,

in the above (a) and (b), one or two methylene groups in the alkylenegroup may be replaced by --O--, --S-- or --NH--, Q is --O-- or --NH--,

Alk is a straight chain or branched chain alkylene group having 1 to 6carbon atoms, which may optionally be intervened by an oxygen atom,

R¹⁰ is a protected amino group, a protected lower alkylamino group, aprotected piperazino group, or a protected hydroxy group,

p and q are both 0 or 1, or when p is 1, q is 0.

The R⁵¹ -R⁹¹ are a group derived from R⁵ -R⁹ by removing the protectinggroup, specifically the groups as defined for R⁵ -R⁹ wherein the groupR¹⁰ is a group obtained by removing the protecting group, that is, thegroup R¹⁰ being an amino group, a lower alkylamino group, a piperazinogroup, or a hydroxy group.

Preferred combinations of the groups R⁵¹ -R⁹¹ are as follows:

(i) R⁷¹ is 3-aminopropyloxy, R⁵¹ is ethyl, and R⁶¹, R⁸¹ and R⁹¹ are eachhydrogen atom,

(ii) R⁵¹ is piperazinomethyl, R⁶¹ and R⁹¹ are each hydrogen atom, andR⁷¹ and R⁸¹ combine to form ethylenedioxy,

(iii) R⁵¹ is aminomethyl, R⁷¹ and R⁸¹ combine to form ethylenedioxy, andR⁶¹ and R⁹¹ are each hydrogen atom,

(iv) R⁵¹ is aminomethyl, R⁷¹ and R⁸¹ combine to form methylenedioxy, andR⁶¹ and R⁹¹ are each hydrogen atom,

(v) R⁶¹ is amino, and R⁵¹, R⁷¹, R⁸¹ and R⁹¹ are each hydrogen atom,

(vi) R⁵¹ and R⁶¹ combine to form amino-substituted trimethylene, R⁷¹ ismethyl, R⁸¹ is fluorine atom, and R⁹¹ is hydrogen atom,

(vii) R⁵¹ and R⁶¹ combine to form trimethylene, R⁷¹ is3-aminopropyl-oxy, R⁸¹ and R⁹¹ are each hydrogen atom,

(viii) R⁷¹ is 3-aminopropyloxy, and R⁵¹, R⁶¹, R⁸¹ and R⁹¹ are eachhydrogen atom.

The salt of the S type 4-hydroxypyranoindolidine compound VIII!, S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound IX! or Stype 4-hydroxypyranoindolidine compound X! includes an alkali metal salt(e.g. sodium salt, lithium salt), and the salt of the camptothecincompound XVI! includes a salt with an inorganic acid (e.g.hydrochloride, sulfate) or a salt with an organic acid (e.g. oxalate,tosylate).

In the above process for the preparation of a camptothecin compound, thereduction and alkanoylation of the S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound II! are carried out in asuitable solvent. The reduction is usually carried out by using acatalyst (e.g. Raney nickel) under hydrogen atmosphere at a roomtemperature to 60° C. The alkanoylation is usually carried out by usinga conventional alkanoylating agent (e.g. a lower alkanoic acid, a loweralkanoic halide, a lower alkanoic acid anhydride) at a room temperatureto 60° C. The solvent to be used in these reactions includes a loweralkanoic acid anhydride (e.g. acetic anhydride), a lower alkanoic acid(e.g. acetic acid), or a mixture of them. When a lower alkanoic acidanhydride, a lower alkanoic acid, or a mixture of them is used in thereduction reaction, they may be used also as an alkanoylating agent, andin such a case, the reduction and the alkanoylation can proceed in asingle step.

The nitrosation and rearrangement of an S type 2-substitutedhydroxy-2-(6-substituted aminomethylindolidinyl)butyric ester compoundV! can be carried out by a similar method to that disclosed in Journalof Medicinal Chemistry, vol. 23, pp. 554-560 (1980) in a suitablesolvent. The nitrosation is carried out under an acidic condition with aconventional nitrosating agent (e.g. sodium nitrite, potassium nitrite)at 0° C. The solvent to be used in this reaction includes a loweralkanoic acid anhydride (e.g. acetic anhydride), a lower alkanoic acid(e.g. acetic acid), or a mixture of them.

The subsequent rearrangement reaction can be carried out by heating theproduct obtained by the above nitrosation at a temperature of 60 to 70°C. The solvent to be used in the rearrangement reaction includes ahalogenated hydrocarbon (e.g. carbon tetrachloride, chloroform,methylene chloride), an ester solvent (e.g. ethyl acetate), anon-aromatic hydrocarbon solvent (e.g. n-hexane), an aromatichydrocarbon solvent (e.g. toluene).

The ester hydrolysis of the S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric ester compoundVI! can be carried out by a conventional method for the ester hydrolysisin a suitable solvent in the presence of a base.

The base to be used in the ester hydrolysis includes inorganic bases,such as an alkali metal hydroxide (lithium hydroxide, sodium hydroxide,potassium hydroxide), an alkaline earth metal hydroxide (e.g. calciumhydroxide), an ammonium hydroxide, an alkali metal carbonate (e.g.sodium carbonate, potassium carbonate), an alkali metal hydrogencarbonate (e.g. sodium hydrogen carbonate), organic bases, such as analkali metal alkoxide (e.g. sodium ethoxide, sodium methoxide), analkali metal phenoxide (e.g. sodium phenoxide), a mono-, di- ortri-lower alkylamine (e.g. methylamine, ethylamine,N,N-dimethyl-1,3-propanediamine, trimethylamine, triethylamine). Thesolvent includes an alcohol solvent (e.g. methanol, ethanol, propanol,isopropanol, butanol), a sulfoxide solvent (e.g. dimethylsulfoxide), ahalogenated hydrocarbon solvent (e.g. methylene chloride), an ethersolvent (e.g. tetrahydrofuran), or a mixture of the organic solvent withwater. When the base is a liquid, it may be used also as a solvent. Thereaction is preferably carried out at a temperature of 0 to 50° C., morepreferably at a room temperature.

When the intramolecular cyclization reaction of an S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolydinyl)butyric ester compoundVI! or an S type 2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acidcompound IX! or a salt thereof and the conversion of the acetal groupinto a ketone group are carried out simultaneously, they can be carriedout in a single step by treating the compound with a suitable acid. Theacid includes an inorganic acid (e.g. hydrochloric acid, sulfuric acid),an organic acid (e.g. trifluoroacetic acid), and a mixture of them withwater. The acid may be used also as a solvent.

On the other hand, when the intramolecular cyclization reaction of an Stype 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolydinyl)-butyric ester compound VI! or an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)-butyric acid compound IX! or asalt thereof is first carried out and thereafter the conversion of theacetal group into a ketone group is carried out, the reactions can becarried out by treating the compound with an acid (e.g. acetic acid,citric acid) weaker than the acid used in the above single step reactionand then treating the resultant with the same stronger acid as used inthe above single step reaction. For example, when the S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound IX! or asalt thereof is treated with a weaker acid, there is obtained an S type4-hydroxypyranoindolidine compound X!, which is converted into an S type4-hydroxypyranoindolidine compound VIII! by treating it with a strongeracid.

The reaction of an S type 4-hydroxypyranoindolidine compound X! or asalt thereof with a lower alkanoic acid XI! or a reactive derivativethereof can be carried out in the presence of a base.

The lower alkanoic acid XI! includes, for example, acetic acid, and thereactive derivative thereof includes an acid anhydride (e.g. aceticanhydride), an acid halide (e.g. acetic chloride), an activated ester(e.g. p-nitro-phenyl ester). The base includes an alkali metal hydride(e.g. sodium hydride, potassium hydride), an alkali metal carbonate(e.g. sodium carbonate, potassium carbonate), an alkali metal hydrogencarbonate (e.g. sodium hydrogen carbonate, potassium hydrogencarbonate), pyridine, and 4-N,N-dimethyl-amino-pyridine. The reaction isusually carried out at a temperature of 0 to 50° C., preferably at aroom temperature.

The subsequent conversion of the acetal group of an S type 4-substitutedhydroxypyranoindolidine compound XII! into a ketone group can be carriedout by treating the compound with a suitable acid. The acid may be thesame acid as used in case of carrying out the intramolecular cyclizationreaction of an S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric acid compound VI! or an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound IX! or asalt thereof and the conversion of the acetal group into a ketone groupin a single step.

The reaction of an S type 4-substituted hydroxypyranoindolidine compoundVII!, an S type 4-hydroxypyranoindolidine compound VIII! or a saltthereof, or an S type 4-substituted hydroxypyranoindolidine compoundXIII! with an o-acylaniline compound XIV! can be carried out by theknown Friedlaender reaction cf. Organic Reactions, vol. 28, pp. 37-202,John Wiley & Sons, Inc., New York (1982)!.

The 4-substituted hydroxypyranoindolidine compound VII! and4-alkanoyloxypyranoindolidine compound XIII! are more stable than an Stype 4-hydroxypyranoindolidine compound VIII! or a salt thereof andfurther are less affect on decomposition of o-acrylaniline compound XIV!during the Friedlaender reaction and thereby can reduce the undesirableby-production of contaminating impurities, and hence, those compoundsare favorably used in the reaction with less amount of the o-acylanilinecompound XIV!, with simple post-reaction treatment such as purificationand can give the desired camptothecin compounds XVI! or a salt thereofin a higher yield.

Moreover, the 4-alkanoyloxypyranoindolidine compound XIII! has amolecular weight much smaller than that of the 4-substitutedhydroxypyranoindolidine compound VII!, and hence, it can be used in theFriedlaender reaction in a smaller amount with a smaller reactionvessel.

The removal of the protecting groups contained in the groups R⁵ -R⁹ canbe carried out by a conventional method suitable to the protectinggroups contained therein. For example, when the amino protecting groupis a benzyloxycarbonyl group, it can be removed by catalytic reductionin the presence of palladium-carbon in a suitable solvent (e.g.tetrahydrofuran, methanol), and when the amino protecting group is atert-butoxycarbonyl group, it can be removed by treating it with an acid(e.g. hydrochloric acid, trifluoroacetic acid) in a suitable solvent(e.g. tetrahydrofuran, methanol, dioxane, methylene chloride).

The removal of the residue R^(o) from an S type 4-substitutedhydroxypyranoindolidine compound VII! or from a camptothecin compoundhaving 20-substituted hydroxy group XV! can be carried out by aconventional ester hydrolysis in the presence of a base in a suitablesolvent. The base and solvent are the same as those used in the esterhydrolysis of an S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound VI!. The reaction may becarried out under cooling, at a room temperature, or with heating.

Besides, the removal of the group R⁴ from the camptothecin compoundhaving 20-alkanoylated hydroxy group XVIII! can be carried out in thesame manner as in the ester hydrolysis of an S type 2-substitutedhydroxy--2-(6-substituted hydroxymethylindolidinyl)butyric estercompound VI! or in the removal of the residue R^(o) from an S type4-substituted hydroxypyranoindolidine compound VII! or from acamptothecin compound having 20-substituted hydroxy group XV!.

The o-acylaniline compound XIV! to be used in the above condensationreactions can be prepared by a process as shown in the followingreaction scheme-1: ##STR24## wherein the symbols are as defined above.

That is, a hydroxyl compound XXII! is treated with an oxidizing agent(e.g. activated manganese dioxide, pyridinium dichromate) to give aketone compound XXIII!, followed by subjecting it to a catalyticreduction in the presence of a suitable catalyst (e.g. palladium-carbon)in a suitable solvent to give the desired o-acylaniline compound XIV!.Moreover, when the protecting group(s) in R⁵ -R⁹ is/are removed by acatalytic reduction, the product may be again introduced with aprotecting group to give an o-acyl-aniline compound XIV!. Besides, ano-acylaniline compound XIV! wherein R⁵ is a lower alkyl group may alsobe prepared by treating a hydroxyl compound XXII! wherein R⁵ is a loweralkenyl group with an oxidizing agent, followed by catalytic reduction.

Furthermore, the hydroxyl compound XXII! wherein the groups R⁵ -R⁹ havea protected amino group, a protected lower alkylamino group, a protectedpiperazino group, or a protected hydroxy group may also be prepared byintroducing a protecting group to the corresponding compound havingunprotected group(s) by a conventional method.

The 2-halo-2-indolidinylacetic ester compound III! used in the presentinvention is novel and can be prepared by a process as shown in thefollowing reaction scheme-2. ##STR25## wherein the symbols are asdefined above.

That is, an indolidine compound XXIV! is reacted with a 1,3-propane-diolcompound XXV! in the presence of an acid (e.g. p-toluenesulfonic acid)or a Lewis acid (e.g. trimethylsilyl chloride) to give anindolidinylmethane compound XXVI!, and the compound XXVI! is treatedwith a carboxylic diester XXVII! in the presence of a base (e.g. sodiumhydride, potassium t-butoxide) in a suitable solvent (e.g. toluene,tetrahydrofuran) to give a 2-indolidinylacetic ester compound XXVIII!,which is further halogenated by a conventional method to give thedesired 2-halo-2-indolidinylacetic ester compound III!.

Among the R type nitrogen-containing fused heterocyclic carboxylic acidcompounds IV! or a salt thereof, the nitrogen-containing fusedheterocyclic carboxylic acid compound XIX! or a salt thereof is noveland can be prepared by reacting an N-unsubstituted nitrogen-containingfused heterocyclic carboxylic acid compound of the formula XXIX!:##STR26## wherein the symbols are as defined above, or a salt thereofwith a sulfonic acid of the formula XXX!:

    YOH                                                         XXX!

wherein the symbol is as defined above, or a reactive derivative or saltthereof by a conventional sulfonamide forming reaction, for example, byreacting a nitrogen-containing fused heterocyclic carboxylic acidcompound XXIX! and a halide (e.g. chloride) of a sulfonic acid XXX! inthe presence of a base (e.g. alkali metal hydroxide).

In the present description and claims, the term "S type" means that theabsolute configuration at 2-position of a 2-substitutedhydroxy-2-indolidinylbutyric ester compound II!, a 2-substitutedhydroxy-2-(6-substituted aminomethylindolidinyl)butyric ester compoundV!, a 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound VI! or a2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound IX! or asalt thereof, or the absolute configuration at 4-position of a4-substituted hydroxypyranoindolidine compound VII!, a4-hydroxypyranoindolidine compound VIII! or a salt thereof, a4-hydroxypyranoindolidine compound X! or a salt thereof, a4-alkanoyloxypyranoindolidine compound XII!, or a4-alkanoyloxypyranoindolidine compound XIII!; and the absoluteconfiguration at 2-position of a 2-(R)-N-tosylprolyloxy!-2-indolidinylbutyric ester compound XXI! are allin "S" configuration.

Throughout the present description and claims, the term "lower alkyl"means a straight chain or branched chain alkyl group having 1 to 6carbon atoms, the term "lower alkanoyl group" and "lower alkanoic acid"mean a straight chain or branched chain alkanoyl group and alkanoic acidwhich have each 1 to 7 carbon atoms, respectively. The term "alkylenegroup" means a straight chain or branched chain alkylene group having 1to 10 carbon atoms.

EXAMPLES

This invention is illustrated in more specifically by the followingexamples and reference examples but should not be construed to belimited thereto.

Example 1

(1) A mixture of ethyl 2-bromo-2- 6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo- 1,2,3,5-tetrahydro-7-indolidinyl! acetate (22.21 g),(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (24.70 g) and potassium carbonate (5.11 g) in dimethylformamide(220 ml) is stirred at 60° C. for 70 minutes. The reaction mixture isextracted with ethyl acetate, and the extract is washed with a saturatedaqueous saline solution and dried over sodium sulfate. After distillingoff the solvent under reduced pressure, the residue is purified with asilica gel column chromatography (eluent; chloroform: ethyl acetate=10:1→6:1) to give ethyl 2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1 -(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate (35.41 g) as colorless powders.

Yield: 92% ##STR27## IR (Nujol, cm⁻¹): 2220, 1750, 1665, 1615

MS (m/z): 738 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.89 and 0.90 (3H, s), 1.10and 1.15 (3H, t, J=7 Hz), 1.33 and 1.35 (3H, s), 2.45-2.60 (2H, m),3.25-3.40 (2H, m), 3.61-3.76 (4H,m), 3.95-4.22 (4H, m), 4.58 and 4.68(1H, d, J=16 Hz), 4.72 and 4.75 (1H, d, J=16 Hz), 5.22 and 5.29 (1H, ddand t, J=3.6 and 5 Hz), 6.01 and 6.04 (1H, s), 6.58 and 6.65 (1H, s),7.02-7.20 (4H, m), 7.37-7.51 (3H, m), 7.54-7.60 (2H, m), 7.62-7.68 (2H,m), 7.85-7.93 (2H, m)

(2) Ethyl 2- (3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(33.63 g) is dissolved in dry dimethylacetamide-toluene (1:1) (330 ml),and thereto is added a 60% oily dispersion of sodium hydride (2.21 g)(1.2 equivalent), and the mixture is stirred at room temperature for 75minutes. To the mixture is added ethyl iodide (36.5 ml) (10equivalents), and the mixture is further stirred at room temperatureovernight. The reaction mixture is extracted with ethyl acetate, and theextract is washed with an aqueous citric acid solution and an aqueoussaturated saline solution, dried over sodium sulfate-magnesium sulfate,and then treated with active carbon (5 g). After distilling off thesolvent under reduced pressure, the residue (35.69 g) thediastereoselectivity of 2S compound and 2R compound=15.2: 1.0 (88% d.e.)which is calculated based on the ratio of integral value at the peak ofδ: 6.71 and 6.46 in NMR spectrum! is dissolved in acetone (60 ml), andthe mixture is stirred at room temperature, and thereto addedportionwise hexane (76 ml) and also added a seed crystal of the desireddiastereomer. The precipitated crystals are collected by filtration,washed with acetone-hexane (60:76) (about 100 ml) to give ethyl (2S)-2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(26.64 g) as colorless crystals.

Yield: 76% ##STR28## m.p.: >82° C. (gradually decomposed) α! _(D) ²⁶:-43.3° (c=1.02, chloroform) IR (Nujol, cm⁻¹): 2220, 1755,1660, 1615

MS (m/z): 766 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.70 (3H, t, J=7.5 Hz),0.85 (3H, brs), 1.02 (3H, t, J=7 Hz), 1.21 (3H, brs), 2.16-2.55 (4H, m),3.35 (1H, dd, J=6.5 and 16 Hz), 3.50 (1H, dd, J=3 and 16 Hz), 3.55-3.70(4H, m), 3.70-3.90 (2H, m), 3.93-4.16 (2H, m), 4.68 (1H, d, J=16 Hz),4.76 (1H, d, J=16 Hz), 5.37 (1H, dd, J=3 and 6.5 Hz), 6.71 (1H, s),7.02-7.10 (1H, m), 7.10-7.20 (3H, m), 7.36-7.50 (3H, m), 7.54-7.59(2H,m), 7.63-7.68 (2H, m), 7.89-7.96 (2H, m)

(3) Ethyl (2S)-2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(23.71 g) and Raney nickel (W-4) (49 g) are dissolved in aceticanhydride-acetic acid (460 ml-190 ml), and the mixture is stirred underhydrogen atmosphere at 50-60° C. After completion of the reaction, thecatalyst is filtered off, and the filtrate is concentrated under reducedpressure, and the residue is purified with a silica gel columnchromatography (eluent; chloroform:methanol=100:1→70:1→60:1) to giveethyl (2S)-2- (3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!-carbonyloxy!-2- 6-(acetylamino)methyl!-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(22.10 g) as pale yellow powders.

Yield: 87% ##STR29## α! _(D) ²⁶ : -14.9° (c=1.01, chlorofonn) IR (Nujol,cm⁻¹): 3405, 3295, 1750, 1660

MS (m/z): 812 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.69 (3H, t, J=7.5 Hz),0.88 (3H, s), 1.02 (3H, t, J=7 Hz), 1.24 (3H, s), 1.96 (3H, s),2.12-2.55 (4H, m), 3.31 (1H, dd, J=6.5 and 16 Hz), 3.41 (1H, dd, J=3 and16 Hz), 3.59 (2H, s), 3.63 (2H, s), 3.84 (1H, dq, J=11 and 7 Hz),3.94-4.14 (3H, m), 4.54 (1H, dd, J=14 and 5.5 Hz), 4.58-4.68 (1H, m),4.63 (1H, d, J=15 Hz), 4.71 (1H, d, J=15 Hz), 5.25 (1H, dd, J=3 and 6.5Hz), 6.74 (1H, s), 7.00-7.19 (5H, m), 7.37-7.50 (3H, m), 7.54-7.64 (4H,m), 7.83-7.89 (2H,m)

(4) Ethyl (2S)-2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-(acetylamino)methyl!-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(30.16 g) is dissolved in acetic anhydride-acetic acid (450 ml-150 ml),and thereto is added sodium nitrite (13.18 g) under ice cooling, and themixture is stirred on an ice-water bath for 4 hours. The reactionmixture is poured onto chloroform (1.5 liter), and undissolvedsubstances are filtered off. The filtrate is evaporated to dryness underreduced pressure, and the residue is mixed with ethyl acetate (900 ml),and the mixture is stirred at 60° C. for 13 hours. The reaction mixtureis diluted with ethyl acetate (700 ml), and the mixture is washed withwater and saline solution, dried over sodium sulfate and then treatedwith active carbon. After distilling off the solvent under reducedpressure, the residue is crystallized from ethyl acetate-hexane to giveethyl (2S)-2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-acetoxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(16.77 g) as colorless prisms.

Yield: 55% ##STR30## m.p.: 145-148° C. α! _(D) ²⁷ : -9.6° (c=1.0,chloroform) IR (Nujol, cm⁻¹): 1755, 1659, 1614

MS (m/z): 813 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.54 (3H, t, J=7.4 Hz),0.88 (3H, s), 1.08 (3H, t, J=7.1 Hz), 1.30 (3H, s), 2.09 (3H, s), 2.24(2H, q like, J=7.6 Hz), 2.47 (2H,t, J=7 Hz), 3.27 (2H, m), 3.65 (4H, m),3.91-4.17 (4H, m), 4.64 (1H, d, J=15.6 Hz), 4.72 (1H, d, J=15.6 Hz),5.13 (1H, dd, J=5.3 and 3 Hz), 5.25 (2H, s), 6.65 (1H,s), 7.01-7.20 (4H,m), 7.37-7.50 (3H, m), 7.55-7.59 (2H, m), 7.65 (2H, d like, J=8.6 Hz),7.90 (2H, d like, J=8.6 Hz)

(5) Ethyl (2S)-2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-acetoxymethyl-1,1-(2,2-dimethyltrimethylene-dioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(1.457 g) is dissolved in a 80% aqueous trifluoroacetic acid solution(15 ml) under ice cooling, and the mixture is stirred at roomtemperature for 2 days. The reaction mixture is concentrated underreduced pressure, and the residue is extracted with chloroform, and theextract is washed with water, and dried over magnesium sulfate. Theextract is distilled to remove the solvent under reduced pressure togive (4S)-7,8-dihydro-4-ethyl-4-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione (1.145 g) as colorless foam.

Yield: 100% ##STR31## IR (Nujol, cm⁻¹): 1746, 1661

MS (m/z): 639 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.82 (3H, t, J=7.5Hz),1.78-2.09 (4H, m), 2.66-2.90 (2H, m), 3.23 (2H, d like, J=4.6 Hz),4.07-4.27 (2H, m), 4.53 (1H, d, J=15.4 Hz 4.69 (1H, d, J=15.6 Hz), 5.01(1H, t, J=5.2 Hz), 5.23 (1H, d, J=18 Hz), 5.49 (1H, d, J=17.9 Hz), 6.58(1H, s), 7.01-7.18 (4H, m), 7.38-7.56 (5H, m), 7.62 (2H, dlike, J=8.6Hz), 7.89 (2H, d like, J=8.6 Hz)

(6) (4S)-7,8-Dihydro-4-ethyl-4-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione (1.145 g) and 1-5'-(3"-(t-butoxycarbonylaminopropyloxy)-2'-aminophenyl!propan-1-one (867mg) are dissolved in acetic acid (15 ml), and the mixture is stirred at60° C. for 47 hours. The reaction mixture is concentrated under reducedpressure, and the resulting crude product is purified with a silica gelcolumn chromatography (eluent; chloroform: ethyl acetate=2:1→1:1) andthen recrystallized from ethyl acetate-hexane to give (20S)-7-ethyl-10-3-(tert-butoxycarbonylamino)propyloxy!-20O- (3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyl!camptothecin(1.11 g) as colorless crystals.

Yield: 67% ##STR32## m.p.: 213-216° C. IR (Nujol, cm⁻¹): 3407, 1763,1753, 1709, 1669, 1614

MS (m/z): 925 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.86 (3H, t, J=7.5 Hz),1.35 (3H, t, J=7.6 Hz), 1.46 (9H, s), 1.88-2.18 (4H, m), 2.94-3.20 (2H,m), 3.34 (2H, d, J=4.8 Hz), 3.42 (2H, q like, J=6.4 Hz), 4.22 (2H, t,J=6 Hz), 4.57 (1H, d, J=15.4 Hz), 4.73-4.81 (1H, br), 4.81 (1H, d,J=15.4 Hz), 4.90 (1H, d, J=18.7 Hz), 5.09 (1H, d, J=18.7 Hz), 5.21 (1H,d, J=4.8 Hz), 5.26 (1H, d, J=17.2 Hz), 5.51 (1H, d, J=17.2 Hz), 6.99(1H, s), 7.01-718 (4H, m), 7.22-7.29 (2H, m), 7.30-7.42 (6H, m), 7.49(1H, dd, J=9.3 and 2.7 Hz), 7.89 (2H, d like, J=8.6 Hz), 8.20 (1H, d,J=9.2 Hz)

(7) (20S)-7-Ethyl-10- 3-(tert-butoxycarbonylamino)propyloxy!-20-O-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyl!-camptothecin(991 mg) is dissolved in water-methanol (6 ml-30 ml), and thereto isadded lithium hydroxide monohydrate (180 mg) under ice cooling, and themixture is stirred at room temperature for 22 hours and further stirredat 50° C. for 4 hours. The reaction mixture is concentrated underreduced pressure, and thereto are added chloroform (20 ml) and aceticacid (4 ml), and the mixture is stirred at room temperature for 19hours. The reaction mixture is diluted with chloroform and water, andthe chloroform layer is washed with water and an aqueous saturatedsaline solution, dried over sodium sulfate. The solvent is distilled offunder reduced pressure to give (20S)-7-ethyl-10-3-(tert-butoxy-carbonylamino)propyloxy!camptothecin. ##STR33## (8) Theobtained (20S)-7-ethyl-10-3-(tert-butoxycarbonylamino)-propyloxy!camptothecin is dissolved inwater-ethanol (5 ml-15 ml) and thereto is added 6.6N hydrochloricacid-ethanol (5 ml), and the mixture is stirred at room temperature for23 hours. The reaction mixture is evaporated to dryness under reducedpressure and the residue is dissolved in ethyl acetate and water. Theethyl acetate layer is further extracted with water, and the aqueouslayers are combined and evaporated to dryness under reduced pressure.The residue is crystallized from isopropanol-water to give(20S)-7-ethyl-10-(3-aminopropyloxy)camptothecin hydrochloride (240 mg)as pale yellow needles.

Yield: 44% overall in the above (7) and (8) ##STR34## m.p.: >218° C.(decomposed) α! _(D) ²⁵ : +9.8° (c=1.0, water)

MS (m/z): 450 (M-Cl⁺); IR (Nujol, cm⁻¹): 3450, 3370, 1745, 1660 NMR (300MHz, DMSO-d₆, δ): 0.88 (3H, t, J=7 Hz), 1.32 (3H, t, J=8 Hz), 1.78-1.95(2H, m), 2.08-2.19 (2H, m), 3.0-3.1 (2H, m), 3.13-3.25 (2H, m), 4.32(2H, t, J=6 Hz), 5.32 (2H, s), 5.43 (2H, s), 7.28 (1H, s), 7.50-7.56(2H, m), 7.99 (3H, brs), 8.11(1H, d, J=10 Hz)

Example 2

(1) The (4S)-7,8-dihydro-4-ethyl-4-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione obtained in Example 1-(5) is treatedin the same manner as described in Example 1-(7) to give(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano 3,4-f!indolidine-3,6,10(4H)-trione. ##STR35## (2) The (4S)-7,8-dihydro-4-ethyl-4-hydroxy- 1H-pyrano 3,4-f!indolidine-3,6,10(4H)-trione is treated in the samemanner as described in Example 1-(6) and -(8) to give (20S)-7-ethyl-10-3-aminopropyloxy)-camptothecin hydrochloride as yellow powder. ##STR36##

Example 3

(1) Ethyl 2-bromo-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(1.28 g),(3R)-N-(4-nitrophenyl-sulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (1.63 g) and potassium carbonate (357 mg) are mixed indimethylformamide (15 ml), and the mixture is stirred at 70° C. for 20minutes. The reaction mixture is treated in the same manner as describedin Example 1-(1) to give ethyl 2-(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(2.10 g) as colorless powders.

Yield: 99% ##STR37## IR (Nujol, cm⁻¹): 2225, 1750, 1665, 1615

MS (m/z): 707 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.89 and 0.90 (3H, s), 1.10and 1.20 (3H, t, J=7 Hz), 1.33 and 1.36 (3H, s), 2.54-2.63 (2H, m),3.30-3.42 (2H, m), 3.60-3.75 (4H, m), 4.00-4.22 (4H, m), 4.50 and 4.57(1H, d, J=15 Hz), 4.78 and 4.83 (1H, d, J=15 Hz), 5.22 and 5.32 (1H, dd,J=3 and 6 Hz), 5.90 and 5.95 (1H, s), 6.48 and 6.54 (1H, s), 7.00-7.23(4H, m), 8.01 and 8.05 (2H, d, J=9 Hz), 8.29 and 8.31 (2H, d, J=9 Hz)

(2) Ethyl 2-(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(25.09 g) is dissolved in dry dimethylacetamide-toluene (1:1) (240 ml),and the mixture is reacted in the same manner as described in Example1-(2) by using a 60% oily dispersion of sodium hydride (1680 mg) (1.2equivalent) and ethyl iodide (54.58 g) (10 equivalents), and the extractis washed with an aqueous citric acid solution and an aqueous saturatedsaline solution, dried over magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue is powdered from ethylacetate - diethyl ether to give ethyl 2-(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyl-trimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(diastereomer mixture) (22.04 g) as colorless powders. Thediastereoselectivity of 2S compound and 2R compound=20.0:1.0 (90% d.e.)which is calculated based on the ratio of integral value at the peak ofδ: 6.85 and 6.41 in NMR spectrum. The colorless powders arerecrystallized from isopropanol to give a pure product (19.32 g) ascolorless crystals.

Yield: 75% ##STR38## m.p.: 181-182° C. α! _(D) ²⁶ : -128.39° (c=0.5,chloroform) IR (Nujol, cm⁻¹): 2217, 1755,1665, 1615

MS (m/z): 735 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.77 (3H, t, J=7.5 Hz),0.85 (3H, s), 0.89 (3H, t, J=7 Hz), 1.20 (3H, s), 2.13 (1H, dq, J=7.3and 15 Hz), 2.27 (1H, dq, J=7.3 and 15 Hz), 2.52-2.57 (2H, m), 3.45-3.66(7H, m), 3.80-3.90 (1H, m), 4.16 (1H, dq, J=7.3 and 13 Hz), 4.36 (1H,dq, J=7.3 and 13 Hz), 4.52 (1H, d, J=15 Hz), 4.87 (1H, dq, d, J=15 Hz),5.48 (1H, dd, J=3 and 6 Hz), 6.85 (1H, s), 7.00-7.10 (1H, m), 7.12-7.23(3H, m), 8.05 (2H, d, J=9 Hz), 8.24 (2H, d, J=9 Hz)

(3) The compound obtained in the above (2) is treated in the same manneras described in Example 1-(3)-(8) or in Example 1-(3)-(5), (7), (6) and(8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride. ##STR39##

Example 4

(1) Ethyl 2-bromo-2-6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(363 mg),(3R)-N-(4-biphenylyl-sulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (472 mg) and potassium carbonate (95 mg) are mixed indimethylformamide (4 ml), and the mixture is stirred at 70° C. for 40minutes. The reaction mixture is treated in the same manner as describedin Example 1-(1) to give ethyl 2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(579 mg) as colorless powders.

Yield=94% ##STR40## IR (Nujol, cm⁻¹): 2225,1750, 1665, 1615

MS (m/z): 766 (MH⁺); NMR (300MHz, CDCI₃, δ): 0.84 (3H, t, J=7.5 Hz),0.94 (3H, t, J=7.5 Hz), 1.11 and 1.16 (3H, t, J=7 Hz), 1.20-1.30 (2H,m), 1.77-1.86 (2H, m), 2.45-2.60 (2H, m), 3.27 3.40 (2H, m), 3.60-3.65(2H, m), 3.75-3.90 (2H, m), 4.00-4.20 (4H, m), 4.55 and 4.80 (2H, m),5.21 and 5.28 (1H, dd, J=3 and 6 Hz), 6.02 and 6.06 (1H, s), 6.57 and6.63 (1H, s), 7.00-7.20 (4H, m), 7.40-7.70 (7H, m), 7.88 and 7.90 (2H,d, J=8 Hz)

(2) Ethyl 2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(564 mg) is dissolved in dry dimethyl-formamide (5 ml), and the mixtureis reacted in the same manner as described in Example 1-(2) by using a60% oily dispersion of sodium hydride (35 mg) (1.2 equivalent) and ethyliodide (1150 mg) (10 equivalents) to give ethyl 2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate(diastereomer mixture) (522 mg) as colorless powders. Thediastereoselectivity of 2S compound and 2R compound=10.8:1.0 (83% d.e.)which is calculated based on the ratio of integral value at the peak ofδ:6.67 and 6.43 in NMR spectrum. ##STR41## IR (Nujol, cm⁻¹): 2220, 1750,1660, 1615

MS (m/z): 794 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.69 (3H, t, J=7.5 Hz),0.81 (3H, t, J=7.5 Hz), 0.87 (3H, t, J=7.5 Hz), 1.03 (3H, t, J=7 Hz),1.22 (2H, q, J=7.5 Hz), 1.67 (2H, q, J=7.5 Hz), 2.20-2.45 (4H, m), 3.34(1H, dd, J=6.5 and 16 Hz), 3.48-3.58 (3H, m), 3.70-3.85 (4H, m),3.98-4.10 (2H, m), 4.67 (1H, d, J=15 Hz), 4.76 (1H, d, J=15 Hz),5.36(1H, dd, J=3 and 6.5 Hz), 6.43 and 6.67 (1H, s), 7.00-7.20 (4H, m),7.40-7.50 (3H, m), 7.56 (2H, d, J=8 Hz), 7.65 (2H, d, J=9 Hz), 7.92 (2H,d, J=9 Hz)

(3) The compound obtained in the above (2) is treated in the same manneras described in Example 1-(3)-(8) or in Example 1-(3)-(5), (7), (6) and(8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride. ##STR42##

Example 5

(1) Ethyl (2S)-2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-acetoxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrateobtained in Example 1-(4) (1.00 g) is dissolved inwater-methanol-tetrahydrofuran (5 ml+20 ml+5 ml), and thereto is addedlithium hydroxide monohydrate (265 mg), and the mixture is stirred atroom temperature for one hour to give lithium (2S)-2-hydroxy-2-6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrate.##STR43## (2) Lithium (2S)-2-hydroxy-2- 6-hydroxymethyl- l,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrateobtained above is dissolved in chloroform (20 ml) and acetic acid (4ml), and the mixture is stirred at room temperature for 16 hours, and tothe reaction mixture is added water, and the mixture is extracted withchloroform three times. The extract is washed with an aqueous saturatedsaline solution, dried over sodium sulfate, and distilled under reducedpressure. The residue is purified by silica gel column chromatography(eluent, chloroform) and recrystallized from ethyl acetate to give(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano3,4-f!indolidine-3,10-dione (276 mg) as colorless needles. Yield: 64%over all in the above (1) and (2) ##STR44## m.p.: 208-210° C. α! _(D) ²⁷: +88.2° (c=0.99, chloroform) IR (Nujol, cm⁻¹): 3340, 2924, 1744

MS (m/z): 350 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.88 (3H, s), 0.99 (3H, t,J=7.3 Hz), 1.29 (3H, s), 1.70-1.92 (2H, m), 2.54 (2H, t, J=7.0 Hz),3.65-3.69 (4H, m), 3.71 (1H, s), 4.14 (2H, dt, J=3.7 and 7.0 Hz), 5.17(1H, d, J=16.2 Hz), 5.60 (1H, d, J=16.2 Hz), 6.81 (1H, s)

(3) The(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano3,4-f!indolidine-3,10-dione is treated in the same manner as describedin Example 1-(5) to give (4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione. ##STR45## (4) The(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano3,4-f!-indolidine-3,6,10(4H)-trione is treated in the same manner asdescribed in Example 1-(6) and (8) to give (20S)-7-ethyl-10-3-(aminopropyloxy)-camptothecin hydrochloride. ##STR46##

Example 6

(1) Lithium (2S)-2-hydroxy-2-6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!butyrateobtained in Example 5-(1) is treated in the same manner as described inExample 1-(5) to give (4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione. ##STR47## (2) The(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione is treated in the same manner asdescribed in Example 1-(6) and (8) to give (20S)-7-ethyl-10-3-(aminopropyloxy)-camptothecin hydrochloride. ##STR48##

Example 7

(1) The(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano3,4-f!indolidine-3,10-dione obtained in Example 5-(2) (50 mg) isdissolved in acetic anhydride (1 ml), and thereto are added pyridine (1ml) and 4-N,N-dimethylaminopyridine (4 mg) under ice cooling, and themixture is stirred at room temperature for 23 hours. The reactionmixture is diluted with chloroform, and the mixture is washed with anaqueous citric acid solution, water and an aqueous saturated salinesolution, and dried over sodium sulfate. After distilling off thesolvent under reduced pressure, the residue is purified by silica gelcolumn chromatography (eluent, chloroform:methanol=40:1) to give(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-acetoxy-1H-pyrano3,4-f!indolidine-3,10-dione (56 mg) as colorless crystals.

Yield: 99% ##STR49## m.p.: 185-188° C. IR (Nujol, cm⁻¹): 2922, 2852,1743, 1671, 1613

MS (m/z): 392 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.87 (3H, s), 0.91 (3H, t,J=7.5 Hz), 1.28 (3H, s), 1.95-2.10 (1H, m), 2.15 (3H, s), 2.15-2.28 (1H,m), 2.40-2.61 (2H, m), 3.55-3.73 (4H, m), 4.12 (2H, t, J=6.8 Hz), 5.27(1H, d, J=17.1 Hz), 5.52 (1H, d, J=17 Hz), 6.31 (1H, s)

(2) The(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-acetoxy-1H-pyrano3,4-f!indolidine-3,10-dione is treated in the same manner as describedin Example 1-(5) to give (4S)-7,8-dihydro-4-ethyl-4-acetoxy-1H-pyrano3,4-f!indolidine-3,6,10(4H)-trione as colorless crystals. ##STR50##m.p.: 197-203° C. IR (Nujol, cm⁻¹): 1742, 1732, 1661, 1610

ESI-MS (0.02M ammonium acetate/methanol, m/z): 323 (MNH₄ ⁺); NMR (300MHz, CDCl₃, δ): 0.92 (3H, t, J=7.5 Hz), 1.94-2.25 (2H, m), 2.16 (3H, s),2.95 (2H, t, J=6.9 Hz), 4.32 (2H, td, J=6.9 and 0.8 Hz), 5.33 (1H, dd,J=18.1 and 0.5 Hz), 5.60 (1H, dd, J=18.1 and 0.4 Hz), 6.76 (1H, s)

(3) The (4S)-7,8-dihydro-4-ethyl-4-acetoxy- 1 H-pyrano3,4-f!-indolidine-3,6,10(4H)-trione is treated in the same manner asdescribed in Example 1-(6) to give (20S)-20-O-acetyl-7-ethyl-10-3-(tert-butoxycarbonylamino)propyloxy!camptothecin as colorless powders.##STR51## m.p.: 173-176° C. IR (Nujol, cm⁻¹): 3370, 1765, 1749, 1696,1657

ESI-MS (m/z): 592 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.97 (3H, t, J=7.5Hz), 1.39 (3H, t, J=7.7 Hz), 1.45 (9H, s), 2.05-2.32 (4H, m), 2.21 (3H,s), 3.14 (2H, q, J=7.7 Hz), 3.41 (2H, q like, J=6.3 Hz), 4.21 (2H, t,J=6.1 Hz), 4.77 (1H, br), 5.23 (2H, d, J=1.1 Hz), 5.40 (1H, d, J=17.2Hz), 5.68 (1H, d, J=17.2 Hz), 7.15 (1H, s), 7.33 (1H, d, J=2.6 Hz), 7.47(1H, dd, J=9.2 and 2.7 Hz), 8.12 (1H, d, J=9.3 Hz)

(4) The (20S)-20-O-acetyl-7-ethyl-10-3-(tert-butoxycarbonylamino)-propyloxy!camptothecin is treated in thesame manner as described in Example 1-(7) and (8) to give(20S)-7-ethyl-10-(3-aminopropyloxy)camptothecin hydrochloride. ##STR52##

Examples 8-12

(1) The corresponding starting compounds are treated in the same manneras described in Example 1-(1) and (2), there are prepared the compoundsas shown in the following Table 1.

                  TABLE 1    ______________________________________    1 #STR53##                           Diastereoselectivety    Ex. No.          X                2S:2R    ______________________________________     8 (1)          --Cl             9.5:1.0     9 (1)          --CH.sub.3       9.0:1.0    10 (1)          --OCH.sub.3      9.0:1.0    11 (1)          2 #STR54##       9.5:1.0    12 (1)          3 #STR55##       10.1:1.0    ______________________________________

(2) The compounds obtained in the above (1) are treated in the samemanner as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7), (6)and (8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride.

Examples 13-16

(1) The corresponding starting compounds are treated in the same manneras described in Example 1-(1) and (2), there are prepared the compoundsas shown in the following Table 2.

                  TABLE 2    ______________________________________    4 #STR56##    Ex. No.           R.sup.0    ______________________________________    13 (1)           5 #STR57##    14 (1)           6 #STR58##    15 (1)           7 #STR59##    16 (1)           8 #STR60##    ______________________________________     Ts: Tosyl group

(2) The compounds obtained in the above (1) are treated in the samemanner as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7), (6)and (8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride.

Examples 17-23

The corresponding starting compounds are treated in the same r asdescribed in Examples 1, 2, 5 or 7, there are prepared the compounds wnin the following Table 3.

                                      TABLE 3    __________________________________________________________________________    9 #STR61##    Ex. No.         R.sup.51      R.sup.61                           R.sup.71                                   R.sup.81                                       R.sup.91    __________________________________________________________________________    17         0 #STR62##    --H --O(CH.sub.2).sub.2 O--                                       --H    18   --CH.sub.2 NH.sub.2                       --H --O(CH.sub.2).sub.2 O--                                       --H    19   --CH.sub.2 NH.sub.2                       --H --OCH.sub.2 O--                                       --H    20   --H           --NH.sub.2                           --H     --H --H    21         1 #STR63##        --CH.sub.3                                   --F --H    22   --(CH.sub.2).sub.3 --                           --O(CH.sub.2).sub.3 NH.sub.2                                   --H --H    23   --H           --H --O(CH.sub.2).sub.3 NH.sub.2                                   --H --H    __________________________________________________________________________     *The number means the substitution position (7position/9-position) at the     camptothecin nucleus.

Example 24

(1) A mixture of ethyl 2-chloro-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(34.11 g),(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (42.33 g) and potassium carbonate (8.67 g) in dimethylformamide(350 ml) is stirred at 60° C. for 45 minutes. The reaction mixture isice-cooled, diluted with ethyl acetate (200 ml), and thereto is added anaqueous saturated sodium hydrogen carbonate solution (300 ml) and isfurther adder water (500 ml). The mixture is extracted with ethylacetate, and the extract is washed, dried, treated with active carbonand filtered. The solvent is distilled off to give ethyl 2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate (66.20 g) as pale yellow foam.

IR (Nujol, cm⁻¹): 2220,1750, 1665, 1615

MS (m/z): 738 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.89 and 0.90 (3H, s),1.10 and 1.15 (3H, t, J=7 Hz), 1.33 and 1.35 (3H, s), 2.45-2.60 (2H, m),3.25-3.40 (2H, m), 3.61-3.76 (4H, m), 3.95-4.22 (4H, m), 4.58 and 4.68(1H, d, J=16 Hz), 4.72 and 4.75 (1H, d, J=16 Hz), 5.22 and 5.29 (1H, ddand t, J=3.6 and 5 Hz), 6.01 and 6.04 (1H, s), 6.58 and 6.65 (1H, s),7.02-7.20 (4H, m), 7.37-7.51 (3H, m), 7.54-7.60 (2H, m), 7.62-7.68 (2H,m), 7.85-7.93 (2H, m)

(2) The ethyl 2-(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl!carbonyloxy!-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetateobtained in the above (1) is treated in the same manner as described inExample 1-(2)-(8) to give(20S)-7-ethyl-10-(3-aminopropyloxy)camptothecin hydrochloride.

Reference Example 1

(1) 6-Cyano-7-methyl-1,5-dioxo-1,2,3,5-tetrahydroindolidine (1.0 g),2,2-dimethyl-1,3-propanediol (6.64 g) and p-toluenesulfonic acid (15 ml)are mixed in dichloroethane (25 ml), and the mixture is heated underreflux for 17 hours with a reflux apparatus provided with Dean-Starkdehydrating device. The reaction mixture is washed with an aqueoussaturated sodium hydrogen carbonate solution and an aqueous saturatedsaline solution, and dried over magnesium sulfate. After distilling offthe solvent under reduced pressure, the residue is purified with asilica gel column chromatography (eluent; chloroform: methanol=50:1) andrecrystallized from methanol to give6-cyano-7-methyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(1.05 g) as colorless needles.

Yield: 72%

m.p.: 225-226° C. IR (Nujol, cm⁻¹): 2222, 1645, 1610

MS (m/z): 275 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.87 (3H, s), 1.30 (3H,s)2.49 (3H, s), 2.53 (2H, t, J=7 Hz), 3.62 (2H, d, J=11 Hz), 3.69 (2H,d, J=11 Hz), 4.15 (2H, t, J=7 Hz), 6.42 (1H, s)

(2) The6-cyano-7-methyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(14.43 g) is mixed in dry toluene (300 ml) and thereto is added a 60%oily dispersion of sodium hydride (9.26 g, 4.4 equivalents), and themixture is stirred on a bath of 80° C. for 2 hours. To the reactionmixture are added diethyl carbonate (24.85 g, 4 equivalents) and ethanol(0.97 g, 0.4 equivalent), and the mixture is reacted at 80° C. for 3hours. While cooling the reaction mixture on an ice bath, a 50% aceticacid (80 ml) is added thereto. The mixture is extracted with chloroform,and the extract is washed with an aqueous saturated saline solution, anddried over magnesium sulfate. After distilling off the solvent underreduced pressure, the residue is purified with a silica gel columnchromatography (eluent; chloroform:ethyl acetate=4:1) and recrystallizedfrom ethyl acetate-ether to give ethyl 2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(14.63 g) as colorless needles.

Yield: 80%

m.p.: 150-151° C. IR (Nujol, cm⁻¹): 2220, 1725, 1650, 1610

MS (m/z): 347 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.87 (3H, s), 1.28 (3H,s), 1.29 (3H, t, J=7.5 Hz), 2.54 (2H, t, J=7 Hz), 3.62 (2H, d, J=11 Hz),3.68 (2H, d, J=11 Hz), 3.79 (2H, s), 4.16 (2H, t, J=7 Hz), 4.22 (2H, q,J=7 Hz), 6.54 (1H, s)

(3) The ethyl 2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(14.60 g) is added to a suspension of a 60% oily dispersion of sodiumhydride (2.02 g, 1.2 equivalent) in dry tetrahydrofuran (240 ml), andthe mixture is stirred at room temperature for 3 hours. To the reactionmixture is added bromine (8.76 g, 1.3 equivalent), and the mixture isstirred at room temperature for 2 hours, and thereto is added ice water.The mixture is extracted with chloroform, and the extract is washed withan aqueous sodium thiosulfate solution and an aqueous saturated salinesolution, and dried over magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue is purified with a silicagel column chromatography (eluent; chloroform:ethyl acetate=4:1) andrecrystallized from ethyl acetate-ether to give ethyl 2-bromo-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(15.66 g) as colorless needles.

Yield: 87%

m.p.: 117-119° C. IR (Nujol, cm⁻¹): 2217, 1725, 1650, 1610

MS (m/z): 427 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.89 (3H, s), 1.28 (3H,s), 1.32 (3H, t, J=7 Hz), 2.5 (2H, t, J=7 Hz), 3.65 (2H, d, J=12 Hz),3.67 (2H, d, J=12 Hz), 4.09-4.22 (2H, m), 4.24-4.35 (2H, m), 5.61 (1H,s), 6.90 (1H, s)

Reference Example 2

(1) 6-Cyano-7-methyl-1,5-dioxo-1,2,3,5-tetrahydroindolidine (5.93 g),2,2-diethyl-1,3-propanediol (49.97 g) and p-toluenesulfonic acid (180ml) are mixed in dichloroethane (150 ml), and the mixture is heatedunder reflux for 22 hours with a reflux apparatus provided withDean-Stark dehydrating device. The reaction mixture is treated in thesame manner as described in Reference Example 1-(1) and recrystallizedfrom methanol to give6-cyano-7-methyl-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(6.67 g) as colorless needles.

Yield: 70%

m.p.: 197-198° C. IR (Nujol, cm⁻¹): 2219, 1655, 1610

MS (m/z): 303 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.83 (3H, t, J=7.5 Hz),0.92 (3H, t, J=7.5 Hz), 1.22 (2H, q, J=7.5 Hz), 1.78 (2H, q, J=7.5 Hz),2.49 (3H, s), 2.52 (2H, t, J=7 Hz), 3.64 (2H, d, J=11 Hz), 3.78 (2H, d,J=11 Hz), 4.14 (2H, t, J=7 Hz), 6.39 (1H, s)

(2) The procedure of Reference Example 1-(2) is repeated by using6-cyano-7-methyl-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine (4.75 g), dry toluene (80 ml), a 60% oilydispersion of sodium hydride (2.76 g, 4.4 equivalents), diethylcarbonate (7.42 g, 4 equivalents) and ethanol (0.37 ml, 0.4 equivalent),and the product is recrystallized from ethyl acetate-ether to give ethyl2-6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(3.71 g) as colorless needles.

Yield: 63%

m.p.: 127-129° C. IR (Nujol, cm⁻¹): 2220, 1745, 1660, 1605

MS (m/z): 375 (MH⁺); NMR (300MHz, CDCl₃, δ): 0.83 (3H, t, J=7.5 Hz),0.91 (3H, t, J=7.5 Hz), 1.23 (2H, q, J=7.5 Hz), 1.29 (3H, t, J=7.5 Hz),1.75 (2H, q, J=7.5 Hz), 2.53 (2H, t, J=7 Hz), 3.62 (2H, d, J=12 Hz),3.77 (2H, d, J=12 Hz), 3.79 (2H, s), 4.15 (2H, t, J=7 Hz), 4.22 (2H, q,J=7 Hz), 6.50 (1H, s)

(3) The ethyl 2- 6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(3.52 g) is added to a suspension of a 60% oily dispersion of sodiumhydride (451 mg, 1.2 equivalent) in dry tetrahydrofuran (60 ml), and themixture is treated at room temperature for 3 hours. To the reactionmixture is added bromine (1.95 g, 1.3 equivalent), and the mixture isstirred at room temperature for 3 hours, and the reaction mixture istreated in the same manner as described in Reference Example 1-(3) andrecrystallized from ethyl acetate-ether to give ethyl 2-bromo-2-6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(2.45 g) as colorless needles.

Yield: 58%

m.p.: 106-108° C. IR (Nujol, cm⁻¹): 2220, 1735, 1660, 1610

MS (m/z): 455 (MH⁺); NMR (300 MHz, CDCl₃, δ): 0.83 (3H, t, J=7.5 Hz),0.92 (3H, t, J=7.5 Hz), 1.26 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7 Hz),1.73 (2H, q, J=7.5 Hz), 2.52 (2H, t, J=7 Hz), 3.61 (1H, d, J=12 Hz),3.62 (1H, d, J=12 Hz), 3.77 (1H, dd, J=2 and 12 Hz), 3.80 (1H, dd, J=2and 12 Hz), 4.16 (2H, m), 4.25-4.35 (2H, m), 5.61 (1H, s), 6.85 (1H, s)

Reference Example 3

Sodium hydroxide (13.6 g) is dissolved in water (300 ml), and therein issuspended (3R)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (30.0 g)and thereto is added tetrahydrofuran (120 ml). To the resulting solutionis added 4-biphenylylsulfonyl chloride (42.9 g), and the mixture isstirred at room temperature for one hour. The reaction mixture isacidified with 10% hydrochloric acid under ice cooling, and is dilutedwith water, and then extracted twice with ethyl acetate. The extract iswashed with water and an aqueous saturated saline solution, dried oversodium sulfate and then treated with active carbon. Undissolvedmaterials are filtered off from the extract, and the solvent isdistilled off under reduced pressure. The residue is recrystallized fromethyl acetate-hexane to give(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (36.5 g) as colorless crystals.

Yield: 55%

m.p.: 195-202° C. α! _(D) ²⁹ : +8.02° (c=1.08, dimethylformamide) IR(Nujol, cm⁻¹): 3300, 2924, 1743, 1456

MS (m/z): 394 (MH⁺); NMR (300 MHz, CDCI₃, δ): 3.10-3.15 (2H, m), 4.48(1H, d, J=15.6 Hz), 4.67 (1H, d, J=15.6 Hz), 4.93 (1H, dd, J=4.0 and 5.3Hz), 6.95-7.20 (4H, m), 7.40-7.53 (3H, m), 7.56-7.69 (4H, m), 7.83-7.88(2H, m)

Reference Example 4

(3R)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid (5.32 g) andsodium hydroxide (2.40 g) are added to a mixture of methylenechloride-water (200 ml--200 ml), and thereto is added dropwise asolution of 4-nitrophenylsulfonyl chloride (6.62 g) in methylenechloride (100 ml) under ice cooling over a period of 30 minutes. Themixture is stirred under ice cooling for 3 hours, and thereto arefurther added sodium hydroxide (1.20 g) and a solution of4-nitrophenylsulfonyl chloride (3.32 g) in methylene chloride (60 ml) inthis order. The mixture is stirred under ice cooling for 2 hours, andfurther stirred at room temperature for 17 hours, and the reactionmixture is diluted with chloroform and 10% hydrochloric acid. Thechloroform layer is collected and washed with water and then with anaqueous saturated saline solution, dried over sodium sulfate and thentreated with active carbon. Undissolved materials are filtered off fromthe chloroform layer, and the solvent is distilled off under reducedpressure. The residue is purified with a silica gel columnchromatography (eluent, chloroform) and recrystallized from ethylacetate-hexane to give(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (4.01 g) as colorless crystals.

Yield: 37%

m.p.: 140° C. α! D²⁵ : +27.2° (c=0.5, ethanol) IR (Nujol, cm⁻¹): 3316,1743,1531,1169

MS (m/z): 361 (M-H⁺); NMR (300 MHz, CDCl₃, δ): 3.15-3.30 (2H, m), 4.40(1H, d, J=l5 Hz), 4.73 (1H, d, J=15 Hz), 5.01 (1H, dd, J=3.7 and 5.7Hz), 7.04-7.20 (4H, m), 7.99 (2H, d, J=9.0 Hz), 8.20 (2H, d, J=9.0 Hz)

Reference Example 5

To a suspension of ethyl 2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(43.41 g) in tetrahydrofuran (600 ml) is added triethylamine (13.94 g)under argon atmosphere at -4° C. and thereto is further added dropwisetrimethylsilyl chloride (14.41 g) at -4 to -3° C. over a period of 5minutes. The mixture is stirred at the same temperature for 55 minutesand thereto is added dropwise a suspension of N-chlorosuccinimide (17.00g) in tetrahydrofuran (400 ml) at -4 to 4° C. over a period of 7minutes. The reaction mixture is further stirred at a temperature of 0°C. to 4° C. for 4.5 hours, and thereto added water (1 liter) at 0° C.,and the mixture is extracted with ethyl acetate. The extract is washed,dried, treated with active carbon, filtered and then distilled to removethe solvent. The residue is recrystallized from ethyl acetate-isopropylether to give ethyl 2-chloro-2-6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl!acetate(40.28 g) as colorless needles.

Yield: 84%

m.p.: 153-155° C. IR (Nujol, cm⁻¹): 2227, 1749, 1662, 1615, 1541, 1311,1241, 1202, 1179, 1161, 1143, 1065, 967, 835, 715

APCIMS (m/z): 381 and 383 (MH⁺); NMR (300 MHz, CDC₃, δ): 0.88 (3H, s),1.28 (3H, s), 1.31 (3H, t, J=7.1 Hz), 2.52-2.58 (2H, m), 3.60-3.70 (4H,m), 4.13-4.21 (2H, m), 4.22-4.37 (2H, m), 5.63 (1h, s), 6.77 (1H, s)

Reference Example 6

(1) 3-Aminopropanol (6.0 g) is dissolved in methylene chloride (50 ml)and thereto is added dropwise di-t-butyl dicarbonate (18.3 g) withstirring under ice cooling. The mixture is stirred at room temperaturefor 2 hours, and the reaction mixture is concentrated and then purifiedwith a silica gel column chromatography to give3-t-butoxycarbonylaminopropanol (13.98 g) as colorless oil.

Yield: 99.9% IR (Neat), v_(max) cm⁻¹ : 3380, 1790

MS (m/z): 176 (M+H⁺); NMR (300 MHz, CDCl₃, δ): 1.45 (9H, s), 1.62-1.72(2H, m), 3.0 (1H, brs.), 3.29 (2H, dd, J=12 Hz and 6 Hz), 3.66 (2H, dd,J=12 Hz and 6 Hz), 4.80 (1H, brs)

(2) 3-t-Butoxycarbonylaminopropanol (10.0 g) is dissolved in methylenechloride (100 ml) and thereto are added triethylamine (8.66 g) and tosylchloride (16.3 g) with stirring under ice cooling. The mixture isstirred at room temperature overnight. The reaction mixture isconcentrated and the residue is dissolved in water-ethyl acetate, andthe organic layer is separated, washed with an aqueous saturated salinesolution, dried over sodium sulfate, and then distilled off the solvent.The residue is purified with a silica gel column chromatography to give3-t-butoxycarbonylaminopropyl tosylate (15.37 g) as pale yellow oil.

Yield: 82% IR (Neat), v_(max) cm⁻¹ : 3400, 3340, 1700, 1600

MS (m/z): 352 (M+Na⁺); NMR (300 MHz, CDCl₃, δ): 1.42 (9H, s), 1.78-1.90(2H, m), 2.45 (3H, s), 3.11-3.22 (2H, m), 4.09 (2H, t, J=6 Hz), 4.5-4.65(1H, m), 7.36 (2H, d, J=8 Hz), 7.77-7.83 (2H, m)

(3) 5-Hydroxy-2-nitrobenzaldehyde (6.0 g) is dissolved in drytetrahyrofuran (90 ml) and thereto is added dropwise vinylmagnesiumbromide (2.3 equivalents) with stirring at -78° C. The temperature ofthe reaction mixture is raised gradually. After completion of thereaction, 1N HCl is added to the reaction mixture, and the mixture isextracted with ethyl acetate, and the organic layer is separated, washedwith an aqueous saturated saline solution, dried over sodium sulfate,and then distilled off the solvent. The residue is purified with asilica gel column chromatography to give1-(5'-hydroxy-2'-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brownpowders.

Yield: 73% m.p.: 126-130° C. IR (Nujol), v_(max) cm⁻¹ : 3440, 1600

MS (m/z): 195 (M⁺); NMR (300 MHz, CDCI₃, δ): 2.4 (1H, br), 5.19 (1H, dd,J=10.5 Hz and 1.5 Hz), 5.38 (1H, dd, J=17 Hz and 1.5 Hz), 5.89 (1H, m),6.08 (1H, ddd, J=17 Hz, 10.5 Hz and 5 Hz), 6.80 (1H, dd, J=9 Hz and 3Hz), 7.22 (1H, d, J=3 Hz), 7.97 (1H, d, J=9 Hz), 9.90 (1H, brs)

(4) 1-(5'-Hydroxy-2'-nitrophenyl)-2-propen-1-ol (2.0 g) is dissolved indry dimethylfornamide (100 ml) and thereto are added sodium iodide (1equivalent) and potassium carbonate and 3-t-butoxycarbonylaminopropyltosylate (1.5 equivalent). The mixture is stirred at 50° C. for 6 hours,and thereto is added ethyl acetate. The mixture is washed with anaqueous saturated saline solution, dried over sodium sulfate. Afterdistilling off the solvent, the residue is purified with a silica gelcolumn chromatography to give 1-5'-(3"-t-butoxy-carbonylaminopropyloxy)-2'-nitrophenyl!-2-propen-1-ol(3.53 g) as pale brown caramel.

Yield: 98% IR (Neat), v_(max) cm⁻¹ : 3400, 1690, 1680

MS (m/z): 375 (M+Na⁺); NMR (300 MHz, CDCl₃, δ): 1.44 (9H, s), 1.96-2.06(2H, m), 2.80 (1H, brs), 3.33 (2H, q, J=6.5 Hz), 4.11 (2H, t, J=6 Hz),4.8 (1H, brs), 5.24 (1H, dd, J=10.5 Hz and 1.5 Hz), 5.42 (1H, dd, J=17Hz and 1.5 Hz), 5.92 (1H, d, J=5 Hz), 6.08 (1H, ddd, J=17 Hz, 10.5 Hzand 5 Hz), 6.86 (1H, dd, J=9 Hz and 3 Hz), 7.25 (1H, d, J=3 Hz), 8.04(1H, d, J=9 Hz)

(5)1-(5'-(3"-t-butoxycarbonylaminopropyloxy)-2'-nitrophenyl)-2-propen-1-ol(9.66 g) is dissolved in chloroform (300 ml) and thereto is addedactivated manganese dioxide (7.2 g), and the mixture is heated withreflux. After completion of the reaction, inorganic materials arefiltered off with celite, and the filtrate is concentrated, and theretois added ethyl acetate. The organic layer is separated, washed with anaqueous saturated saline solution, dried over sodium sulfate. Afterdistilling off the solvent, the residue is purified with a silica gelcolumn chromatography to give 1-5'-(3"-t-butoxycarbonylaminopropyloxy)-2'-nitrophenyl!-2-propen-1-one(6.01 g) as yellow color crystal.

m.p.: 65-71° C. Yield: 63% IR (Neat), v_(max) cm⁻¹ : 3350, 1700

MS (m/z): 351 (M+H⁺); NMR (300 MHz, CDCl₃, δ): 1.44 (9H, s), 1.98-2.18(2H, m), 3.28-3.37 (2H, q J=6.5 Hz), 4.08-4.16 (2H, m), 4.67 (1H, brs),5.85 (1H, d, J=17.5 Hz), 6.02 (1H, d, J=10.5 Hz), 6.62 (1H, dd, J=17.5Hz and 10.5 Hz), 6.82 (1H, d, J=3 Hz), 7.03 (1H, dd, J=9 Hz and 3 Hz),8.17 (1H, d, J=9 Hz)

(6) 1-5'-(3"-t-butoxycarbonylaminopropyloxy)-2'-nitrophenyl)-2-propen-1-one(325 mg) is dissolved in ethanol (15 ml) and thereto is added 10%palladium-carbon (40 mg), and the mixture is stirred under hydrogenatmosphere for 1.5 hour. After removing the catalyst by filtration, thefiltrate is concentrated and purified with a silica gel columnchromatography to give 1-5'-(3"-t-butoxy-carbonylaminopropyloxy)-2'-aminophenyl!propan-1-one (248mg) as yellow powders.

m.p.: 112-115° C. Yield: 83% IR (Nujol), v_(max) cm⁻¹ : 3450, 3400,3340, 1700, 1650

MS (m/z): 323 (M+H⁺); NMR (300 MHz, CDCl₃, δ): 1.21 (3H, t, J=7Hz), 1.45(9H, s), 1.90-2.01 (2H, m), 2.95 (2H, q,J=7.5 Hz), 3.33 (2H, q, J=6.5Hz), 3.97 (2H, t, J=6.5 Hz), 4.48 brs), 5.96 (2H, brs), 6.62 (1H, d, J=9Hz), 6.95 (1H, dd, J=9 Hz and 3 Hz), 7.24 (1H, d, J=3 Hz)

What is claimed is:
 1. A process for preparing an S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound of the formula II!:##STR64## wherein R^(o) is a residue of a nitrogen-containing fusedheterocyclic carboxylic acid having an absolute configuration of "R"which is obtained by removing hydroxy group from the carboxyl group ofsaid carboxylic acid (in which the nitrogen atom contained in theresidue is protected), R¹ and R² are a lower alkyl group, and E is anester residue, which comprises ethylating a 2-substitutedhydroxy-2-indolidinylacetic ester compound of the formula I!: ##STR65##wherein the symbols are as defined above, at 2-position thereof.
 2. Theprocess according to claim 1, wherein R^(o) is a residue obtained byremoving a hydroxy group from the carboxyl group of an R typenitrogen-containing fused heterocyclic carboxylic acid of the formulaXIX!: ##STR66## wherein Y is a substituted or unsubstituted arylsulfonylgroup or an alkylsulfonyl group, and n is 0 or
 1. 3. The processaccording to claim 1, wherein the substituent "Y" is a member selectedfrom the group consisting of a phenylsulfonyl group, a naphthylsulfonylgroup, a biphenylylsulfonyl group and a lower alkylsulfonyl group, and Eis a lower alkyl group, wherein said phenylsulfonyl, naphthylsulfonyland biphenylylsulfonyl groups are optionally substituted with a memberselected from the group consisting of a nitro group, a lower alkylgroup, a lower alkoxy group, a cycloalkyl group, a halogen atom and athienyl group.
 4. The process according to claim 3, wherein Y is a4-biphenylyl-sulfonyl group, or a 4-nitrophenylsulfonyl group, n is 1,R¹ and R² are each a methyl group, and E is a methyl or ethyl group. 5.The process according to claim 2, wherein Y is a phenylsulfonyl group, atosyl group, a 2,4,6-trimethylphenylsulfonyl group, a4-nitrophenylsulfonyl group, a 4-chlorophenylsulfonyl group, a4-methoxyphenylsulfonyl group, a 4-cyclohexylphenylsulfonyl group, a4-(3-thienyl)phenylsulfonyl group, a 2-naphthylsulfonyl group, a4-biphenylylsulfonyl group, a methylsulfonyl group, or an ethylsulfonylgroup.
 6. The process according to claim 5, wherein Y is a tosyl group,a 2-naphthyl-sulfonyl group, a 2,4,6-trimethylphenylsulfonyl group, a4-biphenylylsulfonyl group, or a 4-nitrophenylsulfonyl group and n is 1.7. The process according to claim 5, wherein Y is a tosyl group and n is0.
 8. The process according to claim 5, wherein Y is a4-biphenylyl-sulfonyl group or a 4-nitrophenylsulfonyl group, and n is1.